Method for producing substituted pyridine-carboxylic acids

ABSTRACT

An improved process for the preparation of substituted pyridinecarboxylic acids (II), useful as herbicide intermediates, by ozonolysis of quinolines (I).

This application is a 371 of PCT/EP99/03882 Jun. 4, 1999, nowW099/67217.

Substituted pyridinecarboxylic acids are important raw materials for thesynthesis of herbicides, making the preparation on an industrial scaleof great importance. One method for the preparation of substitutedpyridinecarboxylic acids is the ozonolysis of the correspondingsubstituted quinolines (O'Murchu, Synthesis (1989) pp. 880-882), wherethe quinoline starting material, which has a basic function, isdissolved in a mixture of water and acetic acid by the addition ofsulfuric acid as sulfate, and the ozonolysis is carried out in thissolution. Depending on the substitution of the pyridinecarboxylic acid,the reaction mixture is further oxidized with hydrogen peroxide,particularly if substituted pyridine-2,3-di-carboxylic acids are desiredas reaction products.

An industrially significant product is 2-acetylnicotinic acid, which canbe prepared by ozonolysis of 8-methylquinoline. However, if acorresponding synthesis is carried out on an industrial scale,byproducts arise, which are virtually impossible to remove from theproduct by crystallization as a result of which the high purity requiredfor the further reaction cannot be achieved. As the structure of suchbyproducts which are difficult to remove, substituted pyridinecarboxylicacids alkylated on the pyridine ring have been found. In the case of theozonolysis of 8-methylquinoline for the preparation of 2-acetylnicotinicacid, 2-acetyl-4-methylnicotinic acid and 2-acetyl-6-methylnicotinicacid are found, the 4-methyl derivative remaining in the product in thecase of one crystallization from a solvent such as ethyl acetate, methyltert-butyl ether, acetone, tetrahydrofuran, toluene, methyl isobutylketone, butanol or water.

The cause of this byproduct formation was found in a content of a fewppm of iron in the reaction mixture. In an industrial plant which is atleast partially constructed from constituents whose material isstainless steel, traces of iron are virtually unavoidable, particularlyif, as in the present case, the process is carried out in aqueousstrongly acidic solution.

The object of the present invention was therefore to find an improvedindustrial process for the preparation of substituted pyridinecarboxylicacids by ozonolysis of a correspondingly substituted quinoline in whichthe described byproduct formation can be prevented, even in the presenceof traces of metals such as iron.

Accordingly, the invention provides an improved process for thepreparation of substituted pyridinecarboxylic acids by ozonolysis ofquinolines, which is characterized in that a quinoline of the formula

which is substituted in position 2 and/or 3 and/or 4 by R₃, and inposition 6 and/or 7 by R₄, where R₁ and R₂ are H or a C₁-C₃-alkyl groupand R₃ and R₄ are a group which is inert under the reaction conditions,and at least one of the radicals R₁ and R₂ is not H, is reacted withozone in aqueous acidic solution at temperatures of from −5 to +40° C.,the resulting solution is maintained at a temperature of from 0 to 100°C. for 0.5 to 15 hours with the introduction of oxygen or air fordecomposition of the peroxides formed, and the corresponding substitutedpyridinecarboxylic acid of the formula

in which R₃ is as defined above, and R₅ and R₆ are OH or C₁ to C₃-alkyl,where at least one of the radicals R₅ and R₆ is not OH, is isolated fromthe reaction mixture.

In the process according to the invention, quinolines of the formula Iare converted to substituted pyridinecarboxylic acids of the formula II.Suitable quinolines are substituted here in position 5 or 8 by a methyl,ethyl, isopropyl or n-propyl group. Also, the quinolines may besubstituted in position 2 and/or 3 and/or 4 by hydrogen, C₁-C₃-alkyl oralkoxy groups, halogen etc. Preferably, only one of positions 2, 3 or 4is substituted, and the quinolines used as starting materialparticularly preferably have hydrogen as substituent in position 2, 3and 4. The quinolines suitable as starting materials can also besubstituted in position 6 and/or 7 by a group which is inert under thereaction conditions, such as, for example, by a C₁-C₃-alkyl or alkoxygroup, halogen, etc. Preference is also given to those quinolines whichare substituted in position 8 by a methyl or ethyl group and whereposition 5 is occupied by hydrogen. Examples thereof are8-methylquinoline and 3-ethyl-8-methylquinoline. Particular preferenceis given to using 8-methyl-quinoline.

The starting materials are either available commercially or can beprepared, for example, by the Skraup synthesis, as described, forexample in C. O'Murchu, Synthesis 1989, pp. 880-882.

The corresponding reaction is carried out according to the invention inaqueous acidic solution. Examples of acids which are suitable here aremineral acids, such as sulfuric acid, nitric acid or phosphoric acid.

Where appropriate, an additional solvent, such as, for example, aceticacid, methanol, etc. may also be added. However, the use of acetic acidis preferably avoided so that the ozonolysis is exclusively carried outin aqueous mineral acid as solvent for the substituted quinoline.Particular preference is given to using an aqueous sulfuric acidsolution. The amount of mineral acid is of little significance. If,apart from the aqueous mineral acid, no further solvent (such as e.g.acetic acid) is used, then a sufficient amount of mineral acid must ofcourse be used to form a salt of the quinoline, i.e. in the case ofsulfuric acid 0.5 equivalents or in the case of nitric acid 1equivalent, based on the substituted quinoline, in order to achieve ahomogeneous solution of the starting mixture.

The starting material is dissolved in the aqueous acidic solution, theaim being for the concentration of starting material to be between 2 and30% by weight, preferably between 2.5 and 10% by weight. Lowerconcentrations of starting material increase the yield of the desiredend product. An ozone-bearing stream of O₂ is passed into the resultingsolution until the equivalent amount of ozone or an excess has beenabsorbed. The end and thus the reaction time is determined by theconsumption of the theoretical amount of ozone and can also be readilyascertained from an increased appearance of ozone which occurssimultaneously. The end of the reaction can also be readily ascertainedusing a suitable in process check on the extent of reaction of thesubstituted quinoline.

The temperature of the ozonolysis is −5 to +40° C. Preferably, atemperature of from 0 to +10° C. is chosen. After the ozonolysis, theperoxides which form as intermediates are decomposed by heating thesolution, forming the desired substituted pyridinecarboxylic acid. Thetemperature during the peroxide decomposition can be between 0 and 100°C., preferably at about 50 to 70° C. The time for the peroxidedecomposition naturally depends on the temperature chosen and lasts, forexample at 60° C. for about 2.5 hours. For the process according to theinvention, no further oxidizing agent, such as hydrogen peroxide, isrequired for the peroxide decomposition.

Oxygen is simultaneously introduced into the reaction solution duringthe peroxide decomposition period. Oxygen can be used here in the formof pure oxygen or in the form of air. This measure prevents theformation of end products alkylated in position 4 or 6. The peroxidedecomposition is carried out until a peroxide residual content of atmost 5 mmol/l is achieved. A residue of peroxides can also be destroyedby the addition of a reducing agent, such as, for example, sodiumpyrosulfite, prior to further work-up. If only very small ppm amounts ofiron are present in the reaction mixture, then the formation of thepyridinecarboxylic acids substituted by alkyl groups in the 4- or6-position can be minimized by terminating the peroxide decompositionand reducing peroxide residue which are present using reducing agentssince the free-radical secondary reaction preferably takes place at theend of the peroxide decomposition.

In this case, the introduction of oxygen can optionally be dispensedwith. The byproduct content should not exceed 0.1 percent by weight(determined e.g. by means of HPLC or GC).

The desired end product is isolated from the reaction solution by meansof extraction. The pH during the extraction should be below 4,preferably below 2.5. The desired pH is preferably set using sodiumhydroxide or potassium hydroxide.

Suitable solvents for the extraction are, preferably, toluene, methyltert-butyl ether, ethyl acetate or n-butanol.

Particular preference is given to using ethyl acetate or methyltert-butyl ether as extractant. After the extraction, the organic phaseis concentrated by evaporation, preferably to a concentration of from 10to 30% by weight of product, and, at −10 to +10° C., the desired endproduct crystallizes out.

During the evaporation of the organic solvent, in cases where thissolvent forms an azeotrope with water, then water is also removedazeotropically.

Using the process according to the invention, the desired substitutedpyridinecarboxylic acids of the formula II are obtained in yields of70-80%. The purity of the products is >98%. The process according to theinvention is preferably used for the preparation of 2-acetylnicotinicacid (ANA).

ANA is obtained here in yields of 70-75% and a purity of >98%. Undesiredbyproducts such as 2-acetyl-4-methylnicotinic acid do not form or formonly in negligible amounts.

The pyridinecarboxylic acids prepared according to the invention are, asa result of their purity, particularly suitable as a starting materialfor the preparation of herbicides, and 2-acetylnicotinic acid ispreferably suitable for the preparation of herbicides based onsubstituted semicarbazones.

The invention accordingly also provides for the use of thepyridinecarboxylic acids prepared according to the invention for thepreparation of herbicides.

EXAMPLE 1 (COMPARATIVE EXPERIMENT)

12 kg of 8-methylquinoline (84 mol) were dissolved in 250 liters ofwater and 9.5 kg of 60% strength nitric acid (90 mol). The solution wascooled to 1° C., and a stream of oxygen which contained 60 g/m³ of ozonewas introduced into this solution. This was continued until the residualcontent of 8-methyl-quinoline in the solution was about 1 g/l(determination by means of GC). The solution was then heated at 60° C.for 4 hours for decomposition of the peroxides. The endpoint of theperoxide decomposition was determined by means of titration (potassiumiodide, sodium thiosulfate, starch) . The residual peroxide content was1 mmol/l. Three batches carried out identically were purified. A contentof 12 ppm of iron was found in the peroxide solution.

The pH was adjusted to 1 using 50% strength sodium hydroxide solution,and the solution was extracted countercurrently with ethyl acetate inthe phase ratio 1/1 using a sieve-plate extractor. The extract wasconcentrated to a volume of about 180 liters by distilling off ethylacetate. The solution was cooled to −5° C., and the product was filteredoff using a pressure filter, washed with prechilled ethyl acetate anddried on the pressure filter in vacuo.

This gave 28 kg (67% of theory) of 2-acetylnicotinic acid which,according to GC and HPLC, contained 0. 75% of 2-acetyl-4-methylnicotinicacid.

In this way, batches containing up to 9.1% of 2-acetyl-4-methylnicotinicacid were obtained.

EXAMPLE 2

A stream of oxygen was introduced into 300 ml of an ozonized solutionprepared analogously to Example 1. 40 mg of iron(II) sulfateheptahydrate, corresponding to a content of 25 ppm of iron, were addedto the solution, and the mixture was heated at 60° C. for 2.5 hours withthe further introduction of oxygen. A peroxide content of 3 mmol/l wasfound by titration. Adjustment of the pH to pH 1 with 50% strengthsodium hydroxide solution and extraction with ethyl acetate gave2-acetylnicotinic acid in which no 2-acetyl-4-methylnicotinic acidbyproduct was detectable.

EXAMPLE 3

250 kg of 8-methylquinoline (1.75 kmol) were dissolved in 3200 liters ofwater and 180 kg of 96% strength sulfuric acid (1.75 kmol) . Thesolution was cooled to a temperature of 1° C., and then a stream ofoxygen which contained 50 to 60 g/M³ of ozone was introduced. This wascontinued until the residual content of 8-methylquinoline was about 1gram/liter (determination by means of GC). After the ozonolysis, thereaction mixture was let down into a reactor which contained 2000 litersof water at a temperature of 60° C. 2 m³ of air per hour werecontinuously introduced into the aqueous solution during the peroxidedecomposition. The peroxide decomposition was carried out for 2 hours ata temperature of 60° C. until the peroxide residue content was 3 to 5mmol/liter (titration). 50% strength sodium hydroxide solution was usedto establish a pH of from 1.5 to 2, and the solution was extractedcountercurrently with methyl tert-butyl ether in the methyl tert-butylether/aqueous solution phase ratio=1.5/1 using a sieve-plate extractor.The extract was concentrated to a concentration of about 10% by weightby distilling off methyl tert-butyl ether. The solution was cooled to−10° C., and the product was filtered over a pressure filter, washedwith prechilled methyl tert-butyl ether and dried on the filter invacuo.

This gave 202 kg (70% of theory) of 2-acetyl-nicotinic acid. Accordingto HPLC, the purity was 98.5%; no 2-acetyl-4-methylnicotinic acid wasdetectable as byproduct.

What is claimed is:
 1. An improved process for the preparation ofsubstituted pyridinecarboxylic acids by ozonolysis of quinolines,wherein a quinoline of the formula

which is substituted in position 2 and/or 3 and/or 4 by R₃, and inposition 6 and/or 7 by R₄, where R₁ and R₂ are H or a C₁-C₃-alkyl groupand R₃ and R₄ are a group which is inert under the reaction conditions,and at least one of the radicals R₁ and R₂ is not H, is reacted withozone in aqueous acidic solution at temperatures of from −5 to +40° C.,the resulting solution is maintained at a temperature of from 0 to 100°C. for 0.5 to 15 hours with the introduction of oxygen or air fordecomposition of the peroxides formed, and the corresponding substitutedpyridinecarboxylic acid of the formula

in which R₃ is as defined above, and R₅ and R₆ are OH or C₁ to C₃-alkyl,where at least one of the radicals R₅ and R₆ is not OH, is isolated fromthe reaction mixture.
 2. The process as claimed in claim 1 wherein thequinoline of the formula I used is 8-methylquinoline or3-ethyl-8-methylquinoline.
 3. The process as claimed in claim 1 whereinthe aqueous acidic solution used is an aqueous sulfuric acid, nitricacid or phosphoric acid solution.
 4. The process as claimed in claim 1wherein the reaction with ozone is carried out at 0 to +10° C.
 5. Theprocess as claimed in claim 1 wherein the peroxide decomposition iscarried out at 50-70° C.
 6. The process as claimed in claim 1 whereinoxygen is introduced in the form of pure oxygen or in the form of air.7. The process as claimed in claim 1 wherein the substitutedpyridinecarboxylic acid is isolated from the reaction mixture by meansof extraction.